Process for the preparation of 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines

ABSTRACT

Process, and intermediates useful therein, for obtaining certain 1,2,3,4,5,6-hexahydro-8-(H or OH)-2,6-methano-3-benzazocines valuable as pharmaceutical intermediates by catalytic hydrogenolysis of the corresponding N-benzyl compounds, the latter being produced by Grignard reaction of a benzylmagnesium halide with an N-benzyl-pyridinium halide to yield an N-benzyl-2benzyl-1,2-dihydropyridine, reducing this to the corresponding tetrahydropyridine, and cyclizing this product by heating with a strong mineral acid to obtain the 1,2,3,4,5,6-hexahydro-3-benzyl8-(H or OH)-2,6-methano-3-benzazocine.

United States Patent Albertson et a1.

[72] Inventors: Noel F. Albertson, East Greenbush; William F. Wetterau,Albany, both of NY.

[73] Assignee: Sterling Drug Inc., New York, NY. [22] Filed: July 2,1970 [211 App]. No.: 52,092

Related US. Application Data [62] Division of Ser. No. 670,391, Sept.25, 1967, Pat. No.

[52] US. Cl. ..260/293.52, 260/290 H, 260/293.54, 424/267 [51] Int. Cl.C07d 39/00 [58] Field of Search ..260/293 A, 293.2, 294.7 B, 260/D1G. 13

[56] References Cited UNITED STATES PATENTS 3,341,538 9/1967 Block et a1..260/247.2 3,320,265 5/1967 Clarke ..260/294.7 3,138,603 6/1964 May..260/294.3 3,417,094 12/1968 Dexter ..260/294.7

[15] 3,678,056 [451 July 18,1972

3,476,757 1 H1969 Cross ..260/268 OTHER PUBLICATIONS Dahn et al., Helv.Chim. Acta 35, 1162- 1168 (1952). Hartung et al., Organic Reactions,"Volume VII (Adams et al., editors), John Wiley & Sons, Inc., New York,pp. 263- 266, 275- 278 (1953).

Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas ToddAttorney-Elmer .I. Lawson, B. Woodrow Wyatt, Thomas L. Johnson, RobertK. Bair, William G. Webb, Frederik W. Stonner, Roger T. Wolfe and LynnT. Fletcher [57] ABSTRACT Process, and intermediates useful therein, forobtaining certain l,2,3,4,5,6-hexahydro-8-(H or OH)-2,6-methano-3-benzazocines valuable as pharmaceutical intermediates by catalytichydrogenolysis of the corresponding N-benzyl compounds, the latter beingproduced by Grignard reaction of a benzylmagnesium halide with anN-benzyl-pyridinium halide to yield anN-benzyl-2-benzyl-1,2-dihydropyridine, reducing this to thecorresponding tetrahydropyn'dine, and cyclizing this product by heatingwith a strong mineral acid to obtain thel,2,3,4,5,6-hexahydro-3-benzyl-8-(H or OH)-2,6- methano-3-benzazocine.

4 Claims, No Drawings PROCESS FOR THE PREPARATION OF l,2,3,4,5,6-HEXAHYDRO-2,6-METHANO-3-BENZAZOCINES This application is a division ofour prior copending application Ser. No. 670,39], filed Sept. 25, 1967now U.S. Pat. No. 3,585,203.

This invention relates to chemical processes and chemical compounds.

The invention sought to be patented, in a process aspect, resides in anovel process for preparing chemical compounds which comprises: reactingN-benzy1-3-(R )-4-(R)-pyridinium halide with (p-Y-benzyl) magnesiumhalide in a Gn'gnard reaction to produceN-benzyl-2-(p-Y-benzyl)-3-(R)-4-(R)- 1,2-dihydropyridine; reducing thisdihydropyridine with sodium borohydride in aqueous alcoholic solution toproduce N- benzyl-2-(p-Y-benzyl)-3-(R )-4-(R')-1,2,5,6-tetrahydropyridine; cyclizing this tetrahydropyridine by heating it witha strong mineral acid, or equivalently with aluminum chloride or otherstrong Lewis acid, to yield l,2,3,4,5,6-hexahydro-3-benzyl-6-( R )-1 l-(R )-8-(Z)-2,6- methano-3-benzazocine; and N-debenzylating thiscyclization product by catalytic hydrogenolysis to yieldl,2,3,4,5,6-hexahydro-6-(R)-l1-(R )-8-(Z)- 2,6-methano-3-benzazocine,wherein R' and R are each lower alkyl, Y is hydrogen or lower alkoxy,and Z is hydrogen when Y is hydrogen, and Z is hydroxy when Y is loweralkoxy.

In a particularly preferred procedure for carrying out the above processof this invention, the intermediate N-benzyl-2- p-Y-benzyl )-3-( R )-4-(R)- l ,2,5 ,6-tetrahydropyridine produced by the sodium borohydridereduction step is treated with oxalic acid to formN-benzyl-2-(p-Y-benzyl)-3-(R )-4- (R )-l,2,5,6,-tetrahydropyridineoxalate, which is a crystalline acid-addition salt; and then this saltis isolated and is converted to the free base form by treatment withstrong alkali or, advantageously, the oxalate is used as such in placeof the free base form in the cyclization step of the process.

The invention sought to be patented, in a composition aspect, resides inthe novel chemical compounds designated asl,2,3,4,5,6-hexahydro-3-benzyl-6-(R)-l l-(R )-8-(Z)-2,6-methano-3-benzazocines, wherein R, R and Z have the same significanceindicated hereinabove, obtained as an intermediate in the process ofthis invention.

R and R are the same or different alkyls, and there are included bothstraight and branched chain alkyls, preferably containing one to fourcarbon atoms, for example methyl, ethyl, isopropyl, n-butyl, and thelike. When Y is lower alkoxy, there are included both straight andbranched chain alkyls, preferably containing one to four carbon atoms,for example methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

The halide in the N-benzyl-3-( R )-4-(R)-pyridinium halide and(p-Y-benzyl)magnesium halide reactants is ordinarily chloride, bromide,or. iodide, the preferred halide being iodide in the former and chloridein the latter.

The l,2,3,4,5,6-hexahydro-6-(R)-l 1(R )-8-(Z)-2,6-methano-3-benzazocines produced by the process of this invention arechemical intermediates known to be useful for conversion toN-substituted derivatives thereof having utility as pharmaceuticalagents, for instance as analgesics and as antagonists of stronganalgesic agents, such as morphine and meperidine. The conventionalmethod for obtaining these chemical intermediates involves preparingl,2,3,4,5,6-hexahydro-3-methyl-6-( R)-1 l-( R)-8-(Z)-2,6-methano-3-benzazocine and then N-demethylating it. Thus, (benzyl orpmethoxybenzyl)magnesium halide is reacted with Nvmethyl-3- (R)-4-(R')pyridinium halide to yield N-methyl-2-(benzyl or p-methoxybenzyl)-3-( R )-4-( R l ,2-dihydropyridine which is then reduced to yieldN-methyl-Z-(benzyl or p-methoxybenzyl)-3-(R)-4(R)-1,2,5,6,-tetrahydropyridine, the latter is cyclized by heatingwith a strong mineral acid (or equivalently with aluminum chloride orother strong Lewis acid) to producel,2,3,4,5,6-hexahydro-3-methyl6-(R)-ll- (R)-8-(Z)-2,6methano-3-benzazocine, and removing the N- (or 3-) methylgroup by treatment with cyanogen bromide (after first O-acetylating if Zis hydroxy) to form the N-cyano derivative which is then hydrolyzed toyield the desired N- desmethyl (i.e. N-H) compound,l,2,3,4,5,6-hexahydro-t5-(R )-11(R )-8-(Z)-2,6-methano-3-benzazocine,wherein R, R, Y, and Z all have the same meanings indicated hereinabove.A disadvantage of this prior art process is that the N-demethylationgives relatively poor yields. On the other hand, the new process of theinstant invention gives relatively high yields of product of excellentquality.

The initial step of the new process of this invention involves reactionbetween N-benzyl-3-(R)4-(R)-pyridinium halide and (p-Y-benzyl)magnesiumhalide, under typical Grignard reaction conditions, and isolation of theproduct in conventional fashion.

The N-benzyl-2-(p-Y-benzyl)-3-(R )-4-(R')-1,2- dihydropyn'dine resultingfrom the Grignard reaction is then reduced to the correspondingl,2,5,6-tetrahydropyridine. This reduction is conveniently effectedusing an aqueous alcoholic solution of sodium borohydride. We havediscovered an especially advantageous means for effecting isolation andpurification of the reduction product, i.e. N-benzyl-2-(p-Y-benzyl)-3-(R")-4-(R) -l,2,5,6-tetrahydropyridine. Thus, to a solution of the crudetetrapyridine in a suitable solvent, for instance acetone, there isadded sufiicient oxalic acid to convert the base to its oxalate salt.This crystalline salt is readily isolated in excellent yield and at thesame time there is an unusually clean and efficient separation of thedesired N-benzyl-2-(p-Y- benzyl)-3-(R )-4-(R)-l,2,5,6-tetrahydropyridinespecies of intermediate from undesired by-products arising in theGrignard and reduction reactions. Although the oxalate thus obtained canbe readily converted to the purified free base form, this is notnecessary; instead, it is ordinarily preferred to use the oxalate assuch in the cyclization reaction.

The N-benzyl-2-( p-Y-benzyl)-3-( R )-4-( R)-l ,2,5 ,6-tetrahydropyridine is cyclized by heating it with a strong mineral acid,for example percent phosphoric acid or, preferably, concentratedhydrobromic acid, or if desired, with a strong Lewis acid, to yieldl,2,3,4,5,6-hexahydro-3-benzyl-6 -(R)-ll-(R)-8-(Z)-2,6-methano-3-benzazocine. When Y is lower alkoxy, this group isconverted to hydroxy by dealkylation along with the cyclizationreaction.

Finally, the 3-(or N-) benzyl cyclization product is N-debenzylated bycatalytic hydrogenolysis in the presence of a noble metal catalyst suchas palladium to yield the desired l,2,3,4,5,6-hexahydro-6-(R)-l l-( R)-8-(Z)-2,6-methano-3- benzazocine.

This invention is illustrated by the following examples without,however, being limited thereto.

, EXAMPLE 1 A. A mixture of 30 g. of sodium iodide and ml. of acetone isstirred until solution is complete. To this mixture there is added 25.3g. of benzyl chloride in one portion, and stirring is continued for 1%hours. The reaction mixture is filtered to remove sodium chloride. Theslightly cloudy acetone solution is filtered through diatomaceous silicaand to the filtrate thus obtained there is added 21.4 g. of3,4-dimethylpyridine. The resulting mixture is allowed to standovernight at room temperature and then the precipitate which has formedis collected on a filter and washed with a small amount of acetone.There is thus obtained 60.5 g. of N-benzyl-3,4- dimethylpyridiniumiodide, m.p. l45-l47 C. A second crop of this product, m.p. l37-l40 C.,weighing 3.7 g. is obtained from the filtrate.

A 3-neck flask is flushed with nitrogen and is then charged with 11.0 g.of magnesium turnings, 11.0 g. of magnesium powder, and 60 ml. ofanhydrous diethyl ether. A crystal of iodine and 0.5 g. ofp-methoxybenzyl chloride are added to the mixture, which is then heatedat reflux temperature under anhydrous conditions until the reactionstarts. Heating is stopped, and a solution of 35.8 g. of p-methoxybenzylchloride in 0.6 liter of anhydrous diethyl ether is gradually added tothe reaction mixture at such rate as to maintain gentle refluxing of themixture. The reaction mixture is stirred and refluxed for l% hours andis then filtered to remove excess magnesium. To the filtrate there isadded portionwise 45.7 g. of N-benzyl-3,4- dimethylpyridinium iodide. Acream-orange, gummy semisolid immediately separates from solution. Themixture is stirred and refluxed for 1% hours, during which time thegummy material changes to an almost colorless oil. This reaction mixtureafter standing overnight at room temperature, is mixed with a solutionof 14.0 g. of ammonium chloride in 200 ml. of water. After stirring themixture for one-half hour, the gummy material which separates initiallybecomes a pale yellow solid. This solid is removed by filtration. Theethereal layer in the filtrate is separated from the aqueous layer andis washed with water, and then the ether is removed under reducedpressure to yield an oil residue which weighs 57.5 g. This product isN-benzyl-2-(p-methoxybenzyl)-3,4-dimethyl- 1,2-dihydropyridine.

B. The 57.5 g. of N-benzyl-2-(p-methoxybenzyl)-3,4-dimethyl-l,2-dihydropyridine thus obtained is mixed with 165 ml. ofmethyl alcohol, and the resulting solution, in which some materialremained in suspension, is stirred while adding in a fine stream asolution of 3.9 g. of sodium borohydride in 50 ml. of water. Thereaction mixture is then stirred at room temperature for 19 hours. Themethyl alcohol is distilled from the reaction mixture under reducedpressure, and the residual aqueous mixture is extracted with diethylether. The ethereal solution is separated and is extracted four times:twice with a solution of 8.0 g. of 85 percent phosphoric acid in 150 ml.of water; once with a solution of 1.5 ml. of 85 percent phosphoric acidin 100 ml. of water; and finally with 100 ml. of water. These fourextracts are combined and made strongly alkaline by addition of 35percent aqueous sodium hydroxide solution, and then extracted severaltimes with diethyl ether. The ethereal extracts are combined, and driedover anhydrous sodium sulfate, and the ether is distilled off underreduced pressure. There is thus obtained 32.5 g. of residual oil whichis crude N-benzyl- 2-(p-methoxybenzyl)-3,4-dimethyl-1,2,5,6tetrahydropyridine.

C. The crude tetrahydropyridine base thus obtained is added to asolution of 9.1 g. of anhydrous oxalic acid in 100 ml. of acetone. Aprecipitate forms immediately. The mixture is cooled and filtered, andthe collected solid is washed with a small volume of cold acetone anddried at 61 C. under reduced pressure. There is thus obtained 31.2 g. ofN-benzyl- 3,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate as a whitecrystalline solid which melts at 153l 58 C.

D. A mixture of 53.8 g. of N-benzyl-2-(p-methoxybenzyl)-3,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate, 144 ml. of glacialacetic acid, and 285 ml. of 62 percent hydrobromic acid is refluxed for22 hours. The reaction mixture is then concentrated under reducedpressure, yielding a red-brown residual gum. 800 ml. of isopropylalcohol is added, and the resulting mixture is heated and stirred tobreak up the gummy residue. This forms an incomplete solution having aconsiderable amount of pink solid remaining undissolved. The mixture isconcentrated under reduced pressure to a volume of approximately 250 ml.The concentrated mixture is cooled for 1 hour and then filtered tocollect a pink precipitate. The solid thus collected is washed with asmall volume of cold isopropyl alcohol and dried at 65 C. under reducedpressure. This product, which weighs 358 g. and melts at 130250 C., isdissolved in 450 ml. of boiling anhydrous ethyl alcohol. The alcoholicsolution is cooled slightly and diluted with 550 ml. of anhydrousdiethyl ether and cooled in a refrigerator overnight. The solid whichprecipitates is collected on a filter and dried at 65 C. under reducedpressure. There is thus obtained 23.7 g. of 1,2,3,4,5,6-hexahydro-3-benzyl-6,11 -dimethyl-8- hydroxy-2,6-methano-3-benzazocinehydrobromide as a pale pink solid which melts at 259262 C.

E. A solution of 11.8 g. of l,2,3,4,5,6-hexahydro-3-benzyl- 6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocine hydrobromide in 150 ml.of dimethylformamide is catalytically N-debenzylated using hydrogen at apressure of 800 pounds per square inch at 5055 C. in the presence of 0.3g.

of 10 percent palladium-on-charcoal catalyst. The hydrogenolysis iscomplete in 3 hours, the theoretical amount of hydrogen being absorbed.The catalyst is removed by filtration, and the filtrate is concentratedby evaporation under reduced pressure to a volume of approximately 60ml., cooled, diluted with approximately 150 ml. of concentrated ammoniumhydroxide, and again cooled. The solid which precipitates is collectedon a filter, washed with water, and dried at 65 C. under reducedpressure. There is thus obtained 6 g. of l,2,3,4,5,6-hexahydro-6,11-dirnethyl-8-hydroxy-2,6- methano-3-benzazocine as a pale green solidwhich melts at 234-235 C.

EXAMPLE 2 Proceeding in a manner similar to that described in Example 1above, but using N-benzyl-3-methyl-4-ethylpyridine in place ofN-benzyl-3,4-dimethylpyridine, there is first obtainedN-benzyl-3-methyl-eq-ethy1pyridinium iodide, m.p. 130-133 C. When 30.5g. of this product is interacted with the Grignard reagent prepared from24.8 g. of p-methoxy-benzyl chloride in 64 ml. of anhydrous diethylether, 6.9 g. of magnesium turnings, and 6.9 g. of magnesium powder inanhydrous diethyl ether, there is obtained 36.5 g. ofN-benzyl-2-(pmethoxy-benzyl)-3-methyl-4-ethyl-l,2-dihydropyridine as anamber-colored oil. Reduction of a solution of this product in ml. ofmethyl alcohol with a solution of 2.5 g. of sodium borohydride in 12.5ml. of water yields 16.4 g. of N-benzyl-Z-p-methoxy-benzyl)-3-methyl-4-ethyl- 1 ,2,5,6- tetrahydropyridine as aheavy oil. This base is interacted with 4.4 g. of anhydrous oxalic acidin 50 ml. of acetone to produce 13.3 g. of the oxalate salt of the baseas nearly white crystals, m.p. 143.5l46 C. When 115.7 g. ofN-benzyl-2-(p-methoxybenzyl)-3-methyl-4-ethyl-1,2,5,6-tetrahydropyridineoxalate prepared in this manner is refluxed and stirred with 136 ml. of62 percent hydrobromic acid and 68 ml. of glacial acetic acid for 40hours there is obtained 69.3 g. ofl,2,3,4,5,6-hexahydro-3-benzyl-6-ethyl-1 l-methyl-8-hydroxy-2,6-methano-3-benzazocine hydrobromide in a first crop, m.p. 290293 C.; and a secondcrop of this product, m.p. 295-300 C.,; weighing 14.0 g. is obtained byworkup of the mother-liquor. N-debenzylation of 69.3 g. of this product,using hydrogen at a pressure of 390 pounds per square inch at 60 C., for1 hour, yields 33.9 g. of l,2,3,4,5,6-hexahydro-6-ethyl-l1-methyl-8-hydroxy-2,6-methano-3benzazocine, m.p. 265-269 C. A further crop of thisproduct is recovered from the motherliquor.

EXAMPLE 3 A. A mixture of 20.6 g. of 3,4-dimethylpyridine, 32.9 g. ofbenzyl bromide, and ml. of isopropyl alcohol is refluxed for 3 hours toproduce 51.0 g. of N-benzyl-3,4-dimethylpyridinium bromide, m.p. 202-204C.

A solution of 12.7 g. of benzyl chloride in 70 ml. of anhydrous diethylether is gradually added to 2.7 g. of magnesium turnings in 50 ml. ofdiethyl ether at such a rate as to maintain the refluxing of thereaction mixture. The resulting Grignard reagent is gradually pouredinto a well-stirred refluxing suspension of 16.7 g. ofN-benzyl-3,4-dimethy1pyridinium bromide in 100 ml. of diethyl ether.Steam is applied as necessary to maintain refluxing for 3 hours. Thereaction mixture is poured into a well-stirred mixture of ice watercontaining 10 g. of ammonium chloride. The organic layer of theresulting mixture is separated and the aqueous phase is extracted, inseveral extractions, with a total of 40 m1. of diethyl ether. The etherextracts are combined and concentrated to an oil which weighs 18.1 g.This material is crude N,2-dibenzyl-3,4- dimethyl- 1 ,2-dihydropyridine.

B. The crude N,2-dibenzyl-3,4-dimethyl-1,2- dihydropyridine as obtainedabove is dissolved in 64 ml. of anhydrous ethyl alcohol, and to thissolution there is added, with stirring, a solution of 1.3 g. of sodiumborohydride in 6.4 ml. of water. The reaction mixture is stirred for atotal of 6 hours,

without external heating or cooling, and is then allowed to standovernight at room temperature. The alcohol is evaporated under reducedpressure and the residue is stirred with a mixture of 40 ml. of waterand 50 ml. of diethyl ether. The ethereal layer is separated, and theaqueous layer is extracted with 30 ml. of diethyl ether. This extract iscombined with the initial ethereal layer. The ether is evaporated toyield 16.9 g. of crude N,2-dibenzyl-3,4-dimethyl- 1 ,2,5,6tetrahydropyridine as an oil.

The crude N,2-dibenzyl-3,4-dimethyl- 1 ,2,5,6-

tetrahydropyridine obtained as described above is dissolved in 52 ml. ofacetone and to this solution there is added a solution of 8.06 g. ofoxalic acid dihydrate in 40 ml. of acetone. Separation of crystals fromthe mixture is rapid. The resulting slurry is stored overnight at 3 C.in a refrigerator. The crystalline precipitate is collected, washed with40 ml. of cold C.) acetone, and dried overnight in a vacuum oven at 60C. There is thus obtained 13.2 g. of N,2-dibenzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine oxalate, m.p. 172-l 76 C.

D. A mixture of 18 g. of N,2-dibenzyl-3,4-dimethyl-l,2,5,6-tetrahydropyridine oxalate and 114 ml. of 48 percent hydrobromic acid isgradually heatedto reflux temperature. Solution is complete at 1 15 C.When solid begins to appear it is necessary to drop the temperatureabout 5 C. below reflux to prevent foaming. Heating at 1 l2l 22 C. iscontinued for a total of 12 hours. After cooling the reaction mixture toC. the solid therein is collected on a polypropylene filter cloth andwashed with 80 ml. of cold water. The damp filter cake is slurried in 40ml. of refluxing isopropyl alcohol. The slurry is cooled to 5 C. andfiltered, and the collected solid is washed with ml. of cold (5 C.)isopropyl alcohol and then dried overnight in a vacuum oven at 60 C.There is thus obtained 12.6 g. of l,2,3,4,5,6-hexahydro- 3-benzyl-6,11-dimethyl-2,6- methano-3-benzazocine hydrobromide, m.p. 285-287 C.

E. A solution of 64.3 g. of 1,2,3,4,5,6-hexahydro-3-benzyl-6,1l-dimethyl-2,6-methano-3-benzazocine hydrobromide in 600 ml. ofdimethylformamide is catalytically N-debenzylated during 1 hour usinghydrogen at a pressure of 40-50 pounds per square inch at 45-70 C. inthe presence of 0.65 g. of 60 per cent palladium chloride and 5.9 g. ofcharcoal. The catalyst is removed by filtration, using an additional 200ml. of dimethylformamide as a wash. The solvent is evaporated from thefiltrate under reduced pressure and the residual syrup thus obtained isdissolved in isopropyl alcohol, cooled, and made basic by the additionof 12.6 ml. of concentrated ammonium hydroxide. (Rather than proceedthrough the hemi-hydrobromide salt as described below, if the finalproduct is desired directly in free base form, it is preferable todissolve the residual syrup in water and make the solution basic byaddition of sodium hydroxide solution rather than ammonium hydroxide.)The resulting slurry is cooled overnight at 3 C. in a refrigerator andthen filtered. The crystalline solid thus col lected is washed with 20ml. of cold (3 C.) isopropyl alcohol followed by 20 ml. of pentane, anddried at 60 C. in a vacuum oven.'There is thus obtained 27.9 g. ofl,2,3,4,5,6-hexahydro- 6,1 l-dimethyl-2,6-methano-3-benzazocinehemi-hydrobromide c,,H,,N-% HBr). The filtrate is concentrated todryness, leaving a thick unstirrable mass. This is dissolved in 20 ml.of water, and the solution is made basic by adding 10 ml. of 35 percentaqueous sodium hydroxide solution, and extracted, in severalextractions, with 40 ml. of diethyl ether. The ethereal extracts aredried over sodium hydroxide pellets, the solvent is removed, and theresidue is fractionally distilled under reduced pressure. The fractionboiling at 126-l30 C. at 0.3- 0.5 mm.Hg. has n C.=l.5600, Z 22.7 andweighs 12.6 g. This product is l,2,3,4,5,6-hexahydro-6,l l-dimethyl-2,6-methano-3-benza.zocine.

The l,2,3,4,5,6-hexahydro-6,l l-dimethyl-2,6-methano-3- benzazocinehemi-hydrobromide (27.9 g.) obtained above is converted to the free baseby treating an aqueous solution of the salt with 12 ml. of 35 percentaqueous sodium hydroxide solution. There is thus obtained another 21.3g. of the free base, for a total yield of 33.9 g. of the free base.

We claim:

1. The process which comprises: reacting N-benzyl-3-(R) 4-(R)-pyridinium halide with (p-Y-benzyl)magnesium halide in a Grignardreaction to produce N-benzyl-Z-(p-Y-benzyl)-3- (R )-4-( R)-l,2-dihydropyridine; reducing the N-benzyl-Z-(p- Y-benzyl)-3-(R)-4-(R)-l,Z-dihydropyridine with sodium borohydride in aqueous alcoholicsolution to produce N- benzyl-2-(p-Y-benzyI)-3-(R )-4-(R)-l,2,5,6-tetrahydropyridine; isolating the latter in the form of its crystallineoxalate salt; cyclizing said oxalate salt by heating it with a strongmineral acid to yield l,2,3,4,5,6-hexahydro-3- benzyl-6-( R)-l 1-( R)-8-(Z)-2,6methano-3-benzazocine; and N-debenzylating this cyclizationproduct by catalytic hydrogenolysis to yieldl,2,3,4,5,6-hexahydro-6-(R)-1 l- (R )-8-(Z)-2,6-methano-3-benzazocine,wherein R and R are each lower alkyl, Y is hydrogen or lower alkoxy, andZ is hydrogen when Y is hydrogen and Z is hydroxy when Y is loweralkoxy.

2. The process in accordance with claim 1 wherein each of R and R ismethyl and Y is methoxy.

3. The process in accordance with claim 1 wherein R is ethyl, R ismethyl, and Y is methoxy.

4. The process in accordance with claim 1 wherein each of R and R ismethyl and Y is hydrogen.

2. The process in accordance with claim 1 wherein each of R1 and R2 is methyl and Y is methoxy.
 3. The process in accordance with claim 1 wherein R1 is ethyl, R2 is methyl, and Y is methoxy.
 4. The process in accordance with claim 1 wherein each of R1 and R2 is methyl and Y is hydrogen. 